1. Carcinogenesis Main changes in the cell physiology that lead to formation of the malignant phenotype: Main changes in the cell physiology that lead to formation of the malignant phenotype: A- Self-sufficiency in growth signals B- Insensitivity to growth-inhibitory signals C- Evasion of apoptosis D- Limitless replicative potential E- Sustained angiogenesis F- Ability to invade and metastsize

2. Genomic Instability Enabler of malignancy Enabler of malignancy Due to defect in DNA repair genes Due to defect in DNA repair genes Examples: Examples: Hereditary Nonpolyposis colon carcinoma(HNPCC) Hereditary Nonpolyposis colon carcinoma(HNPCC) Xeroderma pigmentosum Xeroderma pigmentosum Familial breast cancer Familial breast cancer

3. Genomic Instability Familial breast cancer: Familial breast cancer: Due to mutations in BRCA1 and BRCA2 genes Due to mutations in BRCA1 and BRCA2 genes These genes regulate DNA repair These genes regulate DNA repair Account for 80% of familial breast cancer Account for 80% of familial breast cancer They are also involved in other malignancies They are also involved in other malignancies

4. Molecular Basis of multistep Carcinogenesis Cancer results from accumulation of multiple mutations Cancer results from accumulation of multiple mutations All cancers have multiple genetic alterations, involving activation of several oncogenes and loss of two or more tumor suppressor genes All cancers have multiple genetic alterations, involving activation of several oncogenes and loss of two or more tumor suppressor genes

5. Molecular Basis of multistep Carcinogenesis

6. Tumor progression Many tumors become more aggressive and acquire greater malignant potential…this is called “ tumor progression” …not increase in size!! Many tumors become more aggressive and acquire greater malignant potential…this is called “ tumor progression” …not increase in size!! By the time, the tumor become clinically evident, their constituent cells are extremely heterogeneous By the time, the tumor become clinically evident, their constituent cells are extremely heterogeneous

8. Karyotypic Changes in Tumors Translocations: Translocations: In CML : t(9,22) …” Philadelphia chromosome” In CML : t(9,22) …” Philadelphia chromosome” In Burkitt Lymphoma : t(8,14) In Burkitt Lymphoma : t(8,14) In Follicular Lymphoma : t(14,18) In Follicular Lymphoma : t(14,18) Deletions Deletions Gene amplification: Gene amplification: Breast cancer : HER-2 Breast cancer : HER-2

9. TranslocationsGene amplification deletion

10. NEOPLASIA Lecture 5 Maha Arafah, M.D, KSFP Abdulmalik Alsheikh, M.D, FRCPC Host defense Effect of a tumor on the host Laboratory Diagnosis Foundation block 2014 Pathology Foundation block 2014 Pathology

11. Objectives Define host defense against cancer Define host defense against cancer Define tumor grade and clinical stage. Define tumor grade and clinical stage. Define cachexia and its cause. Define cachexia and its cause. Define paraneoplastic syndrome, and know examples of tumors associated with endocrinopathies, osseous changes, and vascular and hematologic changes. Define paraneoplastic syndrome, and know examples of tumors associated with endocrinopathies, osseous changes, and vascular and hematologic changes. Be familiar with the general principles, value, procedures, and applications of biopsy, exfoliative and aspiration cytology, and frozen section. Be familiar with the general principles, value, procedures, and applications of biopsy, exfoliative and aspiration cytology, and frozen section. List some examples of tests used to diagnose cancer by immunohistochemistry and flowcytometry. List some examples of tests used to diagnose cancer by immunohistochemistry and flowcytometry. Discuss the use of molecular diagnostic testing in the setting of cancer diagnosis and prognosis. Discuss the use of molecular diagnostic testing in the setting of cancer diagnosis and prognosis.

12. Host defense Tumor Antigens: Tumor Antigens: Tumor-specific antigens: present only on tumor cells Tumor-specific antigens: present only on tumor cells Tumor-associated antigens: present on tumor cells and some normal cells Tumor-associated antigens: present on tumor cells and some normal cells

13. Host defense Tumor antigens may: Tumor antigens may: Result from gene mutations: P53, RAS Result from gene mutations: P53, RAS Be products of amplified genes: HER-2 Be products of amplified genes: HER-2 Viral antigens: from oncogenic viruses Viral antigens: from oncogenic viruses Be differentiation specific: PSA in prostate Be differentiation specific: PSA in prostate Oncofetal antigens: CEA, Alpha fetoprotein Oncofetal antigens: CEA, Alpha fetoprotein normal embryonic antigen but absent in adults….in some tumors it will be re-expressed, e.g: colon ca, liver cancer normal embryonic antigen but absent in adults….in some tumors it will be re-expressed, e.g: colon ca, liver cancer

14. Host defense Antitumor mechanisms involve: Antitumor mechanisms involve: Cytotoxic T lymphocytes (CD8) Cytotoxic T lymphocytes (CD8) Most efficient mechanism for killing cancer cells Natural killer cells Natural killer cells Macrophages Macrophages Humoral mechanisms : Humoral mechanisms : Complement system Complement system Antibodies Antibodies

15. Clinical features Tumours cause problems because : Tumours cause problems because : Location and effects on adjacent structures: (1cm pituitary adenoma can compress and destroy the surrounding tissue and cause hypopituitarism). (0.5 cm leiomyoma in the wall of the renal artery may lead to renal ischemia and serious hypertension). Tumors may cause bleeding and secondary infections lesion ulcerates adjacent tissue and structures

17. EFFECT OF A TUMOR ON THE HOST Secondary fracture Secondary fracture

18. Clinical features Effects on functional activity hormone synthesis occurs in neoplasms arising in endocrine glands: adenomas and carcinomas of β cells of the islets of the pancreas produce hyperinsulinism. Some adenomas and carcinomas of the adrenal cortex elaborate corticosteroids. aldosterone induces sodium retention, hypertension and hypokalemia Usually such activity is associated with benign tumors more than carcinomas.

19. Clinical features Cancer cachexia Usually accompanied by weakness, anorexia and anemia Severity of cachexia, generally, is correlated with the size and extend of spread of the cancer. The origins of cancer cachexia are multifactorial: anorexia (reduced calorie intake) increased basal metabolic rate and calorie expenditure remains high. general metabolic disturbance

20. Clinical features Paraneoplastic syndromes They are symptoms that occur in cancer patients and cannot be explained. They are diverse and are associated with many different tumors. They appear in 10% to 15% of pateints. They may represent the earliest manifestation of an occult neoplasm. They may represent significant clinical problems and may be lethal. They may mimic metastatic disease.

21. Clinical features The most common paraneoplastic syndrome are: Hypercalcemia Cushing syndrome Nonbacterial thrombotic endocarditis The most often neoplasms associated with these syndromes: Lung and breast cancers and hematologic malignancies

22. Paraneoplastic syndromes SyndromeMechanismExample Cushing's Syndrome ACTH -like substanceLung oat cell carcinoma Hypercalcemia Parathormone -like substance Lung squamous cell carcinoma Renal cell carcinoma Breast carcinoma Hyponatremia Inappropriate ADH secretion Lung oat cell carcinoma Polycythemia Erythropoietin -like substance Cerebellar haemangioma Renal cell carcinoma Trousseau's Syndrome Hypercoagulable state Pancreatic carcinoma Various carcinomas Hypoglycemia Insulin -like substanceVarious carcinomas and sarcomas Carcinoid Syndrome 5 hydroxy -indoleacetic acid - 5HIAA Metastatic malignant carcinoid tumors

23. Clinical Features Grading : Grading : Grade I, II, III, IV Grade I, II, III, IV Well, moderately, poorly differentiated, anaplastic Well, moderately, poorly differentiated, anaplastic Staging : Staging : Size Size Regional lymph nodes involvement Regional lymph nodes involvement Presence or absence of distant metastasis Presence or absence of distant metastasis TNM system TNM system

24. Grading of Malignant Neoplasms GradeDefinition IWell differentiated IIModerately differentiated IIIPoorly differentiated IVNearly anaplastic

25. Oat cell carcinima of the lung Undifferenciated carcinoma Grade IV Adenocarcinoma of the colon Well differenciated carcinoma Higher grade means: a lesser degree of differentiation and the worse the biologic behavior A well differentiated neoplasm is composed of cells that closely resemble the cell of origin. Poorly differentiated neoplasms have cells that are difficult to recognize as to their cell of origine

26. Clinical Staging T (primary tumor): T1, T2, T3, T4 T (primary tumor): T1, T2, T3, T4 N (regional lymph nodes): N0, N1, N2, N3 N (regional lymph nodes): N0, N1, N2, N3 M (metastasis): M0, M1 M (metastasis): M0, M1

27. TNM staging system in cancer

28. Staging of Malignant Neoplasms StageDefinition TisIn situ, non-invasive (confined to epithelium) T1Small, minimally invasive within primary organ site T2Larger, more invasive within the primary organ site T3Larger and/or invasive beyond margins of primary organ site T4Very large and/or very invasive, spread to adjacent organs N0No lymph node involvement N1Regional lymph node involvement N2Extensive regional lymph node involvement N3More distant lymph node involvement M0No distant metastases M1Distant metastases present

29. Laboratory Diagnosis Morphologic methodes Biochemical assays Molecular diagnosis

30. Laboratory Diagnosis Microscopic Tissue Diagnosis Microscopic Tissue Diagnosis. the gold standard of cancer diagnosis. Several sampling approaches are available: Excision or biopsy Frozen section fine-needle aspiration Cytologic smears

31. Histologic methods

32. Slide 8.56 cytologic methods

33. Immunohistochemistry

34. Laboratory Diagnosis Biochemical assays: Biochemical assays: Useful for measuring the levels of tumor associated enzymes, hormones, and tumor markers in serum. Useful in determining the effectiveness of therapy and detection of recurrences after excision Elevated levels may not be diagnostic of cancer (PSA). Only few tumor markers are proved to be clinically useful, example CEA and α- fetoprotein.

36. Laboratory Diagnosis Molecular diagnosis Molecular diagnosis Polymerase chain reaction (PCR) example: detection of BCR-ABL transcripts in chronic myeloid leukemia. Fluorescent in situ hybridization (fish) it is useful for detecting chromosomes translocation characteristic of many tumors Both PCR and Fish can show amplification of oncogenes (HER2 and N-MYC)

37. Molecular diagnosis DNA microarray analysis Expression of thousands of genes are studied. Different tissue has different pattern of gene expression. Powerful tool useful for subcategorization of disease e.g. Lymphoma - confirmation of morphologic diagnosis - illustration of genes involved in certain disease and possible therapy.